Pharmaceutical solid preparations are sometimes coated with sustained release coating, enteric coating or bitter-taste masking coating with a view to reducing side-effects of the drug comprising in them, reducing the administration frequency, improving the effect of the drug, suppressing bitter taste, stabilizing the drug, or the like. Granules having a high sphericity are one of the dosage forms suited for film coating thereon. Such granules are called spherical base granules.
As a production process of spherical base granules, a process of carrying out extrusion granulation using a drug and an excipient as raw materials and then spheronizing the resulting granules (extrusion/spheronization process), a process of coating the surface of spherical core particles with a drug (layering process) (refer to, for example, Patent Document 1 and Patent Document 2), and the like are known.
In the layering process, granules are produced by spraying a layering liquid to spherical core particles to coat the spherical core particles with a coating layer. Specific examples of it include a process (power coating process) of simultaneously supplying a drug in powder form and an aqueous solution of a binder; and a process (layering-liquid spraying process) of supplying a suspension of drug particles or an aqueous solution of the drug.
The layering process is suited as a process for producing spherical base granules, because spherical base granules having a high sphericity and a narrow particle size distribution can be obtained by using spherical core particles having a high sphericity and a narrow particle size distribution.
Among the layering processes, the powder coating process has low flexibility with respect to coating conditions and has relative difficulty in stable and high-yield production of spherical base granules. The layering-liquid spraying process is, on the other hand, a superior layering process because of easy condition setting and high productivity. In particular, when the layering-liquid spraying process is applied to the production of spherical base granules comprising a drug having a medium level of water solubility, spherical base granules excellent in various physical properties can be obtained in a high production yield by using a suspension of the drug as the layering liquid.
When the layering-liquid spraying process is applied to a production process of spherical base granules comprising a drug (easily water-soluble drug) having high water solubility, however, agglomeration of the spherical base granules is likely to occur. It is therefore necessary to reduce the concentration of the layering liquid or reduce the spray rate of the layering liquid.
The reduction in the concentration or spray rate of the layering liquid causes problems such as surface roughening due to a reduction in a filling density of a drug-comprising layer and a reduction in the mechanical strength of the spherical base granules. In addition, it leads to prolongation of a layering time and causes a further problem such as reduction in the production efficiency of the spherical base granules.
Under present circumstances, it is therefore very difficult to apply the layering process to the production of spherical base granules comprising an easily water-soluble drug.
It is known to add various additives to the layering liquid for the purpose of preventing agglomeration, preventing separation of layered drug controlling a dissolution rate of the drug, or stabilization (refer to, for example, Patent Document 3 or Patent Document 4). These prior arts are not developed for preventing agglomeration when an easily water-soluble drug is used and therefore do not have a sufficient effect for preventing agglomeration when a easily water-soluble drug is used. Moreover, when an inorganic substance is added, continuous stirring of the layering liquid is required in order to prevent precipitation.    Patent Document 1: Japanese Patent Laid-Open No. Sho 63-301816    Patent Document 2: Japanese Patent Laid-Open No. Hei 7-53355    Patent Document 3: Japanese Patent Laid-Open No. Hei 9-165329    Patent Document 4: Published Japanese Translations of PCT International Patent Publication No. 2003-509439.